An animal model of the heterosexual transmission of HIV would provide a system in which to test and define cofactors involved in the transmission of HIV. This project has demonstrated that cell-free SIV can be transmitted to female rhesus macaques by vaginal inoculation and to male rhesus macaques by penile inoculation. By placing human seminal plasma in the vagina, the dose of cell-free SIV necessary for transmission is lowered and as little as 1 TCID50 can infect some animals. Recent studies have shown that some animals inoculated intravaginally with low doses of cell-free SIV become transiently viremic and the infection does not spread to systemic lymphoid tissue. This intriguing finding is being vigorously pursued and these observations may lead to a more complete understanding of the pathogenesis of heterosexual HIV transmission. Nonoxynol-9 containing spermicides can prevent the genital transmission of SIV. Thus these compounds may be useful for preventing the sexual transmission of HIV. The pathogenesis of sexual transmission of HIV has been explored by using in-situ-hybridization and immunohistochemistry to localize SIV in the reproductive tract of infected animals. This work has shown that target cells for SIV infection are present in the vaginal epithelium and the foreskin of the penis. Using immunohistochemistry, the architecture of the genital mucosal immune system in the genital tract of normal female rhesus macaques was defined. The mucosal immune response to the genital transmission of SIV has been assessed. Newly developed elisa assays were used to detect the levels of IGG. IGM, IGA in vaginal secretions and it has been determined that there is only a weak IGG antibody response to SIV in genital secretions. An understanding of the genital secretory immune system may eventually lead to the development of vaccines against other sexually transmitted diseases.